CN115317497A - Application of liquiritin in preparing thoracic aorta vasodilation medicine - Google Patents
Application of liquiritin in preparing thoracic aorta vasodilation medicine Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention provides application of liquiritin in preparing thoracic aorta vasodilation drugs and corresponding pharmaceutical compositions, in particular application in treating cardiovascular and cerebrovascular diseases, such as angina pectoris, heart failure, and the like. The invention discloses that liquiritin applied to isolated thoracic aortic annulus of PE pre-contracted rat has obvious expansion effect, and the action mechanism of liquiritin expanding blood vessel is related to voltage-dependent potassium channel and ATP sensitive potassium channel.
Description
Technical Field
The invention relates to the field of cardiovascular and cerebrovascular diseases, and particularly provides application of liquiritin in preparing thoracic aorta vasodilators and a corresponding pharmaceutical composition.
Background
At present, the prevalence rate and the death rate of cardiovascular and cerebrovascular diseases are continuously increased in the global range, and the serious influence is caused on the human health. It is important to find a convenient and easily available medicament with low price for effectively treating cardiovascular and cerebrovascular diseases.
Research proves that the generation of cardiovascular and cerebrovascular diseases is closely related to vascular endothelium incompletion and endothelial function damage. At present, drugs for vasodilatation are classified into endothelium-dependent drugs and endothelium-independent drugs, while the clinically common drugs are all endothelium-dependent vasodilatation drugs, such as Angiotensin Converting Enzyme Inhibitors (ACEI), HMG-COA reductase inhibitors, angiotensin II receptor blockers (ARB), endothelin Receptor Antagonists (ERA), levo-arginine, receptor blockers, etc., which have poor therapeutic effects on cardiovascular diseases patients with impaired vascular endothelial function. Therefore, the search for non-endothelium dependent vasodilators is of great clinical interest.
The mechanism of action of non-endothelium-dependent drugs is mainly related to + Channel correlation, k + The channels play an important role in regulating the processes of relaxation and contraction of vascular smooth muscle. After potassium channels are activated, hyperpolarization of the cell membrane is induced, resulting in Ca 2+ Channels are closed, ca 2+ The inflow is reduced, and the blood vessel is dilated.
The root and stem of licorice is a commonly used Chinese herbal medicine, and the root and stem of licorice is listed as the top grade in Shen nong Ben Cao Jing, which is called the king of the most popular herb, but rarely used in Jing Fang. The liquorice is used as a traditional Chinese herbal medicine, has wide application range and various chemical components, mainly contains triterpenes, flavonoids and coumarins, wherein the flavonoids are components with stronger biological activity obtained from liquorice extract, and the Liquiritin (systematic name: 4', 7-dihydroxy dihydroflavone-4' -O-beta-D-glucopyranoside) is an important monomer active component in the liquorice flavonoid compound, belongs to flavanones and has wide pharmacological activity. The liquiritin is used as a main active ingredient in liquorice, and most researches show that the liquiritin can play a role in protecting the cardiovascular system and the liver, and whether the cardiovascular protection role is related to vasodilatation or not is not reported.
Disclosure of Invention
In one aspect, the application provides the use of liquiritin in the preparation of a thoracic aorta vasodilator drug
Further, the thoracic aorta vasodilator is a drug for treating angina.
Further, the thoracic aorta vasodilator is a drug for treating heart failure.
Further, the thoracic aortic vasodilator is a drug for dilating thoracic aortic blood vessels.
Furthermore, the medicine is used for treating cardiovascular and cerebrovascular diseases.
Further, liquiritin in the drug acts through ATP-sensitive potassium channels.
In another aspect, the present invention provides a thoracic aortic vasodilator comprising liquiritin as an effective ingredient.
Further, the medicament is used for treating angina, heart failure, or for thoracic aortic vasodilation.
Further, liquiritin in the drug acts through ATP-sensitive potassium channels.
Further, the medicine is in an oral or injection dosage form.
Further, the medicine also comprises pharmaceutic adjuvant.
The available dosage forms of the application include but are not limited to injections such as injection, powder injection and the like, oral preparations such as tablets, capsules, oral liquid and the like, throat or nasal sprays, external preparations such as ointments, sprays, patches and the like; preferably injection and oral preparation. The medicine can also contain other medicines for dilating thoracic aorta blood vessels, and treating angina pectoris and ischemic cerebral apoplexy, or be combined with the medicines; that is, different drugs in other therapeutic combinations can be prepared into the same formulation; may also be provided in the same package in the same or different dosage forms; or in the same or different dosage forms in separate packages.
Those skilled in the art can select suitable excipients for the drugs to which this application relates based on general knowledge in the pharmaceutical arts, and the classes of excipients that can be used include, but are not limited to, solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, binders, gas generants, and the like.
The chemical name of glycyrrhizin described in this application is 4', 7-dihydroxydihydroflavone-4' -O-beta-D-glucopyranoside. The chemical formula is as follows:
drawings
FIG. 1: effect of LQ on the basal tension endothelial intact thoracic aortic vascular ring.
FIG. 2 is a schematic diagram: effect of LQ on PE pre-contracted endothelial intact thoracic aortic vascular ring.
FIG. 3: effect of LQ on PE pre-constriction of the de-endothelialized thoracic aortic vascular ring.
FIG. 4: comparison of LQ to PE pre-contracted endothelial integrity and de-endothelialized thoracic aortic vascular ring relaxation rates.
FIG. 5: effect of L-NAME on LQ diastolic thoracic aortic vascular ring action.
FIG. 6: effect of INDO on LQ diastolic thoracic aortic vascular ring effects.
FIG. 7: baCl 2 Influence on LQ diastolic thoracic aortic vascular ring action.
FIG. 8: effect of TEA on the vasodilatory action of LQ on thoracic aortic vascular rings.
FIG. 9: effect of 4-AP on LQ diastolic thoracic aortic vascular ring action.
FIG. 10: effect of Gli on LQ diastolic thoracic aortic vascular ring action.
Detailed Description
The present invention will be further specifically described in connection with animal experiments
Experimental materials:
animals: SPF grade Sprague Dawley (SD) rats, male, weighing 220-330g, provided by the animal laboratory animal center of the university of ningxia medical science, animal certification No.: SCXK 2015-0001. Animals are raised in an environment with proper temperature and humidity, and are free to eat and drink water.
Drugs and reagents:
liquiritin (abbreviated LQ, english, liquiritin, shanghai-derived leaf Biotechnology Co., ltd., CAS: 551-15-5), phenylephrine (English, PE, shanghai Hefeng pharmaceutical Co., ltd., batch No. 07150801); acetylcholine chloride (English, ACh, beijing Solebao science and technology Co., ltd., batch No. 601H 013); glibenclamide (Glibenclamide, shanghai Yi En chemical technology Co., ltd., lot number: 131426); barium chloride (BaCl) 2 Shanghai yuan leaf biotechnology limited, lot No.: X11J10J 79704); tetraethylammonium (English, TEA, shanghai Bide pharmaceutical science, inc., lot number: ASU 324); 4-aminopyridine (English, 4-AP, tokyo Kasei Kogyo society, batch number: RWZZC-NC); L-Nitro-arginine methyl ester (English, L-NAME, shanghai Yi En chemical technology Co., ltd., batch No. 120373); indomethacin (English, INDO, shanghai Allantin Biotechnology Co., ltd., batch No.: C1723020); sodium bicarbonate (a license number of XK 13-011-00027, available from Dalocheng chemical reagent works, tianjin); potassium chloride (Hangzhou national pharmaceutical Co., ltd., approval No. H33021574); glucose (the license number of the Daoyou chemical reagent factory in Tianjin is XK 13-201-001100); calcium chloride (mao chemical reagent, penguin, tianjin); monopotassium phosphate (a national reagent factory, beichen, tianjin, lot number: 20150626); magnesium sulfate heptahydrate (mao chemical reagent factory, tianjin, enterprise logo); sodium chloride (Tianjin, damao chemical reagent factory, license number: XK 13-011-00027); the water is double distilled water.
Preparing K-H nutrient solution by adding 0.35g KCl and 0.29g MgSO into 1000ml double distilled water respectively 4 ·7H 2 O、0.28g CaCl 2 、0.16g KH 2 PO 4 2.0g glucose, 6.92g NaCl, 2.21 g NaHCO 3 In a beaker, stir until the drug is completely dissolved. Prepared at present in clinical use by using 10mmol L -1 Adjusting the pH value to 7.4 by NaOH, and storing in a constant-temperature water bath at 37 ℃ for later use.
The instrument comprises:
HV1403 constant temperature perfusion system of isolated tissue organs (Chengtai Union software Co., ltd.); BL-420S biological function experimental system (Chengdu Taiyuan software Co., ltd.); model HW-500 super constant temperature water bath (Gengtai alliance software Co., ltd.).
Example 1 preparation of isolated rat thoracic aortic vascular Ring
Collecting SPF healthy SD male rats weighing 180-220g, placing in an operation board after anaesthetizing, cutting the chest to find and separate the thoracic aorta, rapidly transferring the removed thoracic aorta into general (95% 2 + 5％CO 2 ) Carefully removing fat and connective tissue around blood vessels from the K-H solution of the mixed gas, and shearing the blood vessels into blood vessel rings with the length of 3-4 mm. And preparing a part of the vascular ring into an endothelial removal model by adopting a method of rubbing the inner surface of the vascular ring by a cotton swab. Suspending the vascular ring in a bath containing K-H solution preheated at 37 deg.C, fixing one end, connecting the tension transducer with the biological signal acquisition system at the other end, and continuously processing to 95% 2 And 5% of CO 2 Mixing gas, adjusting base tension to 2.0g, stabilizing for 60 min, changing solution 1 time every 20 min, and administering KCl (60 mmol. L) -1 ) Stimulating to reach peak value, flushing with K-H solution for 3 times to reach maximum contraction amplitude of blood vessel ring. Warp PE (10) -6 mol·L -1 ) The vascular ring is preshrunk, after the tension is stabilized, ach (10. Mu. Mol/L) is added, if the vasodilation reaches more than 80%, the endothelium is considered to be intact. If the vasodilation is less than 10%, de-endothelialization may be considered.
Example 2 methods of observation and study
Observing the influence of liquiritin on the vascular ring tension of the basal state:
the endothelial intact vascular ring was divided into a blank control group and an LQ administration group. After stabilization, adding LQ cumulatively every 5min to make the final concentration increase to 3, 10, 30, 100 and 300 μmol/L; the blank control group was added with an equal volume of DMSO solution, and the change in the tension thereof was observed, and the diastolic rate was calculated, and (%) = diastolic amplitude of vascular rings after liquiritin addition/maximum ring systolic amplitude of PE-induced vessels × 100%. The effect of cumulative administration of LQ on the base tension vascular ring was explored.
The effect of liquiritin on PE pre-systolic vascular ring tension was observed:
respectively collecting complete endothelial and de-endothelial vascular rings, and treating with PE (10) -6 mol/L) after pre-shrinking is stabilized, adding LQ cumulatively every 5min to make its final concentration increase to 3, 10, 30, 100 and 300 mumol/L; the blank control group is added with an equal volume of DMSO solution, the change of the tension is observed, and the relaxation rate is calculated by the same method. The effect of cumulative administration of LQ on PE to pre-constrict endothelial integrity and the de-endothelialized vascular ring was explored.
The action mechanism of liquiritin on thoracic aorta vascular ring is explored:
collecting rat isolated thoracic aorta vascular ring with intact endothelium, and respectively using L-NAME,10 -4 mol/L and INDO, 10 - 5 And incubating the vascular ring preshrinked by PE for 20 minutes in mol/L, after stabilization, adding LQ cumulatively every 5 minutes to increase the final concentration to 3, 10, 30, 100 and 300 mu mol/L, incubating the blank control group with equal volume of K-H nutrient solution, observing the influence of L-NAME and INDO on the effect of LQ vasodilating vascular ring, recording the tension change, and calculating the diastolic rate by the same method.
Taking rat isolated thoracic aorta vascular ring with intact endothelium, respectively using 4-AP,10 -3 mol/L、TEA， 10 -2 mol/L、glibenclamide，10 -5 mol/L and BaCl 2 10 -3 Incubating PE preshrinked de-endothelialized vascular ring at mol/L for 20 min, stabilizing, adding LQ at 5min intervals to make final concentration increase to 3, 10, 30, 100 and 300 μmol/L, incubating with equal volume of K-H nutrient solution in blank control group, and observing 4-AP, TEA, glibenclamide and BaCl 2 And (4) recording tension change and calculating the diastolic rate on the influence of the LQ on the diastolic blood vessel ring effect by the same method.
Example 3 results of the experiment
Experimental data are expressed as mean ± standard deviation and analyzed using SPSS26.0 statistical software. The comparison between the two groups was performed using independent samples t test, and P <0.05 indicated that the difference was statistically significant.
Effect of cumulative concentration of LQ on basal state vascular ring tone:
FIG. 1 shows that LQ had no effect on the endothelial intact, basal tension thoracic aortic vessel ring in the concentration range of 3-300. Mu. Mol/L, with no difference compared to the control group, P > 0.05.
Effect of cumulative concentrations of LQ on PE pre-systolic vascular ring tone:
FIGS. 2-4 show that LQ, at concentrations ranging from 3-300. Mu. Mol/L, dilates both the endothelial intact and the de-endothelialized PE pre-contracted thoracic aortic vascular rings, with significant differences compared to the control group, P < 0.001, no difference in PE pre-contracted endothelial intact and de-endothelialized thoracic aortic vascular ring diastolic rates, P > 0.05.
Effects of L-NAME and INDO on LQ diastolic Ring action:
FIGS. 5-6 show that PE pre-contracted vascular rings incubated with the NO (nitric oxide) synthase inhibitor L-NAME were not significantly different compared to the control group, P > 0.05; the PE preshrinked vascular rings incubated with the cyclooxygenase inhibitor INDO showed no significant difference compared with the control group, and P was > 0.05.
Potassium channel blocker BaCl 2、 Effect of 4-AP, TEA, and Glibenclamide on LQ diastolic Ring action
FIGS. 7-10 show inward flow potassium channel blockers BaCl 2 The incubated PE preshrinked vascular rings have no significant difference compared with a control group, and P is more than 0.05; the PE pre-contracted vascular ring incubated by the calcium-activated potassium channel blocker TEA has no significant difference compared with a control group, and P is more than 0.05; compared with a control group, the PE preshrinked vascular ring incubated by the ATP sensitive potassium channel blocker Glibenclamide has obvious difference, and P is less than 0.001; the PE preshrinked vascular rings incubated with the voltage-dependent potassium channel blocker 4-AP have significant difference compared with the control group, and P is less than 0.001.
Claims (12)
1. Use of liquiritin in preparing thoracic aorta vasodilator is provided.
2. The use according to claim 1, wherein the thoracic aortic vasodilator drug is a drug for the treatment of angina.
3. The use according to claim 1, wherein the thoracic aortic vasodilator drug is a drug for the treatment of heart failure.
4. The use of claim 1, wherein the thoracic aortic vasodilator drug is a drug that expands thoracic aortic vessels.
5. The use according to any one of claims 1 to 4, wherein the medicament is a medicament for the treatment of cardiovascular and cerebrovascular diseases.
6. The use according to claims 1-5, wherein the cardiovascular and cerebrovascular disease is angina pectoris, heart failure, pulmonary hypertension, coronary heart disease, cerebral stroke and/or peripheral vasospastic disease.
7. The use according to any one of claims 1-6, wherein liquiritin in the medicament acts through a voltage-dependent potassium channel or an ATP-sensitive potassium channel.
8. A thoracic aortic vasodilator comprising liquiritin as an active ingredient.
9. The medicament of claim 8, wherein the medicament is for the treatment of angina, heart failure, or for thoracic aortic vasodilation.
10. The medicament of claim 8 or 9, wherein liquiritin in the medicament acts through a voltage-dependent potassium channel or an ATP-sensitive potassium channel.
11. The medicament or use according to any one of claims 1 to 10, wherein the medicament is in an oral or injectable dosage form.
12. The medicament or use according to claim 11, wherein the medicament further comprises a pharmaceutical excipient.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003053336A2 (en) * | 2001-12-19 | 2003-07-03 | The Quigley Corporation | Methods for the treatment of peripheral neural and vascular ailments |
| CN102125576A (en) * | 2010-01-14 | 2011-07-20 | 北京联合大学应用文理学院 | Application of liquiritin in preparing medicine for treating cardiovascular and cerebrovascular diseases |
| CN104873527A (en) * | 2015-05-19 | 2015-09-02 | 中国人民解放军第二军医大学 | Natural medicine composition used for treating cardiovascular diseases |
| CN104873932A (en) * | 2015-05-19 | 2015-09-02 | 中国人民解放军第二军医大学 | Traditional Chinese medicine extract composition used for treating cardiovascular diseases and preparation method thereof |
| CN110664820A (en) * | 2019-09-16 | 2020-01-10 | 宁夏医科大学 | Application of glycyrrhetinic acid in preparation of drugs for dilating thoracic aorta blood vessels |
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- 2022-01-13 CN CN202210038440.0A patent/CN115317497A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003053336A2 (en) * | 2001-12-19 | 2003-07-03 | The Quigley Corporation | Methods for the treatment of peripheral neural and vascular ailments |
| CN102125576A (en) * | 2010-01-14 | 2011-07-20 | 北京联合大学应用文理学院 | Application of liquiritin in preparing medicine for treating cardiovascular and cerebrovascular diseases |
| CN104873527A (en) * | 2015-05-19 | 2015-09-02 | 中国人民解放军第二军医大学 | Natural medicine composition used for treating cardiovascular diseases |
| CN104873932A (en) * | 2015-05-19 | 2015-09-02 | 中国人民解放军第二军医大学 | Traditional Chinese medicine extract composition used for treating cardiovascular diseases and preparation method thereof |
| CN110664820A (en) * | 2019-09-16 | 2020-01-10 | 宁夏医科大学 | Application of glycyrrhetinic acid in preparation of drugs for dilating thoracic aorta blood vessels |
Non-Patent Citations (1)
| Title |
|---|
| 万嘉洋等: "次乌头碱和甘草苷及甘草次酸配伍对急性心力衰竭大鼠的动态保护研究", 中华中医药杂志, vol. 34, no. 2, pages 746 - 750 * |
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